FDA-approved Abl/EGFR/PDGFR kinase inhibitors show potent efficacy against pandemic and seasonal influenza A virus infections of human lung explants
Robert Meineke,
Sonja Stelz,
Maximilian Busch,
Christopher Werlein,
Mark Kühnel,
Danny Jonigk,
Guus F. Rimmelzwaan,
Husni Elbahesh
Affiliations
Robert Meineke
Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
Sonja Stelz
Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
Maximilian Busch
Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
Christopher Werlein
Department of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
Mark Kühnel
Department of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany; Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
Danny Jonigk
Department of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany; Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School (MHH), Carl-Neuberg-Straße 1, 30625 Hannover, Germany
Guus F. Rimmelzwaan
Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany
Husni Elbahesh
Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine in Hannover (TiHo), Bünteweg 17, 30559 Hannover, Germany; Corresponding author
Summary: Influenza viruses (IVs) cause substantial global morbidity and mortality. Given the limited range of licensed antiviral drugs and their reduced efficacy due to resistance mutations, repurposing FDA-approved kinase inhibitors as fast-tracked host-targeted antivirals is an attractive strategy. We identified six FDA-approved non-receptor tyrosine kinase-inhibitors (NRTKIs) as potent inhibitors of viral replication of pandemic and seasonal IVs in vitro. We validated their efficacy in a biologically and clinically relevant ex vivo model of human precision-cut lung slices. We identified steps of the virus infection cycle affected by these inhibitors and assessed their effect(s) on host responses. Their overlapping targets suggest crosstalk between Abl, EGFR, and PDGFR pathways during IAV infection. Our data and established safety profiles of these NRTKIs provide compelling evidence for further clinical investigations and repurposing as host-targeted influenza antivirals. Moreover, these NRTKIs have broad-spectrum antiviral potential given that their kinase/pathway targets are critical for the replication of many viruses.
